Rheumatoid arthritis (RA) is one of the most common autoimmune diseases and a leading cause of chronic pain affecting over three million people in Europe alone. Rheumatoid arthritis affects 1 to 2% of the population. According to Medical Expenditure Panel Survey (MEPS) data, in the US the total costs incurred towards the treatment of rheumatoid arthritis and related arthritis in 2003 was $128 billion; the average per person cost is currently $8500. Each year, arthritis and its associated complications results in over 750,000 hospitalizations and 36 million outpatient visits. Up to 15% of people inflicted with any type of arthritis suffer from a reduction in the amount of physical activities they can perform. Typically when physical activity is reduced patients tend to develop depression because of their lack of independence and freedom.
In the UK there are around 400,000 adults with rheumatoid arthritis and arthritis is the most common condition for which people receive Disability Living Allowance. Over half a million people receive DLA as a result of arthritis (representing more than 18 percent of all DLA claimants), which is more than the total for heart disease, stroke, chest disease and cancer combined.
RA is an inflammatory disease of the synovial joints, which generally affects wrists, fingers, knees, feet, and ankles on both sides of the body. RA causes inflammation of the synovial membranes that line and protect the joints and tendons and, allow smooth and free movement of joints. Inflammation of the synovial membranes causes swelling of the affected joints and eventually leads to progressive cartilage destruction and erosion of bone, impairing range of movement and leading to deformity.
RA is an ongoing, progressive disease that also affects other organs of the body and can result in profound disability and life threatening complications. Hence, RA is a major cause of disability with a significant associated morbidity and mortality.
The onset age of RA is variable, ranging from children to individuals in their 90s. The prevalence of RA in populations of Western Europe and USA is approximately 1% with a female to male ratio of 3:1. Further, the total annual economic impact of rheumatoid arthritis is estimated at approximately £35 billion in Western Europe.
At a cellular level, the synovium is made up of a well organized matrix containing proteoglycan aggregates, a network of capillaries and lymphatic vessels and resident fibroblast and macrophage like cells. In RA, however, the synovium becomes infiltrated by T-helper cells, B cells, macrophages and plasma cells. Further, the synovium becomes hyperplastic and locally invasive at the interface between cartilage and bone causing destruction of articular cartilage, subchondral bone and periarticular soft tissue resulting in joint damage, deformity and profound disability in the long run (see FIG. 1).
It is now well established that angiogenesis (growth of new blood vessels from pre-existing vessels) in the synovium has a significant contribution to etiology and progression of this disease. Indeed, synovial angiogenesis may precede other pathological features of RA since synovial hypercellularity necessitates a compensatory increase in the number and density of synovial blood vessels.
The ultimate goals for the treatment of rheumatoid arthritis are to prevent joint damage, prevent loss of function and decrease the pain associated with RA. Non-steroidal anti-inflammatory drugs (NSAID) and disease modifying anti-rheumatic drugs (DMARD) are currently the major forms of treatment for RA, but they often come with significant side effects. NSAID can cause stomach irritation, gastrointestinal ulcers and kidney damage. The side effects of DMARDs depend on the type of drug used. Azathioprine increases the risk of infection, liver damage, hair loss and diarrhoea. Cyclosporine causes kidney damage, hypertension and enlarged gums. Chloroquine group causes gastritis, diarrhoea and vision problems. Gold salt can cause swelling of the tongue, bleeding gums, skin rash and kidney damage. Methotrexate can cause liver damage and bone marrow suppression. Sulfasalazine can cause gastrointestinal upset and allergic reactions. The newer biologic response modifiers depress the immune system and can cause reactivation of latent infections like tuberculosis.
Therapy for RA has been significantly improved in the last decade by the introduction of recombinant antibodies targeting a range of cytokines, T cells and B cells.
Since the initial approval of Etanercept, and shortly thereafter Infliximab, three additional TNF-neutralizing antibodies (Adalimumab, Certulizumab pegol and Golimumab) have been approved. Further, recombinant antibodies targeting T-cell [and/or dendritic cell], (Abatacept), B-cells, (Rituximab), and the receptor for cytokine IL-6, (Tocilizumab) have also been approved by the FDA for treatment of RA (Taylor and Feldmann 2009 Nat Rev Rheumatol 5(10): 578-582), (Isaacs 2009 Arthritis Res Ther 11(3): 225).
However, despite the obvious impact of the current therapies, prolonged treatment-free remission has not been obtained. Sustained and high magnitude clinical response is achieved by a minority (Taylor and Feldmann 2009, as above) and approximately 20-40% of patients do not respond to anticytokine therapy (Kremer 2001 Annals of Internal Medicine 134(8): 695-706). Also, the current therapeutics exhibit a number of associated adverse affects such as increased risks of infections and malignancies which make their persistent administration undesirable (Taylor and Feldmann 2009, as above).
Therefore, there is still a major unmet clinical need in RA and a requirement for alternative therapeutic options having a greater frequency of remission induction and improved safety profile with less systemic toxicity.